If you have all the DLCs from the subscription service or the Humble Bundle, and it is only a question of enabling/disabling, I would definitely disable Conquest of Paradise to not have busted and bugged North American natives. I don't own Mare Nostrum myself, so I can't tell you if its impact is actually negative or just not very positive. We have had patches where Golden Century was worth disabling just so Spain wouldn't be #1 great power every single game, but that doesn't seem to be the case currently.
As for other settings, a lot of people don't know that turning off the "Limit Idea Groups" option is Ironman compatible. It is good to keep it on for multiplayer, and for beginners to avoid a certain pitfall, but otherwise you can just turn it off.